Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001754.3 | Alternative | 6190 nt | 400–1842 |
| NM_001754.4 | RefSeq Select | 5967 nt | 191–1633 |
| NM_001754.5 | MANE Select | 5971 nt | 195–1637 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The RUNX1 S413Ffs*187 variant is a truncating mutation in the RUNX1 gene, a tumor suppressor involved in hematopoietic differentiation. Functional evidence indicates that truncating mutations in RUNX1 can inhibit its function, contributing to oncogenesis and predisposing individuals to hematologic malignancies such as leukemia, lymphomas, and myelodysplastic syndromes.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 270 bp |
| Donor Loss (DL) | 0.0 | -357 bp |
| Acceptor Gain (AG) | 0.0 | 186 bp |
| Donor Gain (DG) | 0.0 | 456 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects." The evidence for this variant shows: NM_001754.4:c.1237dupT causes a frameshift leading to a premature termination codon and is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant (frameshift) in RUNX1, where loss of function is a known mechanism of disease.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: S413Ffs*187 does not match any previously established pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 applies to de novo occurrences (Moderate = ≥1 proven; Supporting = ≥1 assumed). The evidence for this variant shows: No data on de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 states: "Not applicable if variant meets PVS1." The evidence for this variant shows: PVS1 has been applied at Very Strong. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: Strong = ≥4 probands, Moderate = 2–3 probands, Supporting = 1 proband. The evidence for this variant shows: No proband data reported. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: Variant affecting one of the specified RHD residues; Supporting Strength: Variant affecting other residues 89–204." The evidence for this variant shows: S413Ffs*187 lies outside the RHD (residues 49–187). Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Variant must be completely absent from all population databases." The evidence for this variant shows: Not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 applies to recessive disorders requiring observation in trans with another pathogenic variant. The evidence for this variant shows: No evidence of biallelic inheritance in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 applies to protein length changes due to in-frame insertions or deletions. The evidence for this variant shows: It is a frameshift duplication, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Supporting)
According to VCEP guidelines, the rule for PM5 is: "PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98." The evidence for this variant shows: c.1237dupT results in a frameshift S413Ffs*187 downstream of codon 98. Therefore, this criterion is applied at Supporting strength because it is a truncating variant downstream of c.98.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 applies to assumed de novo occurrences. The evidence for this variant shows: No data on de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 applies to segregation in multiple affected family members. The evidence for this variant shows: No segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 applies to missense variants in a gene with low benign missense rate. The evidence for this variant shows: It is not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 applies to missense or intronic variants with computational predictions. The evidence for this variant shows: It is a frameshift and SpliceAI score 0, which does not predict a splice impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 applies when a highly specific phenotype is observed. The evidence for this variant shows: No phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 applies to variant classified as pathogenic by a reputable source without primary data. The evidence for this variant shows: Not found in ClinVar or other expert reports. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 applies to variants with MAF≥0.15%. The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 applies to MAF between 0.015% and 0.15%. The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 applies when variant is observed in healthy individuals. The evidence for this variant shows: No such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 applies to normal functional assay results. The evidence for this variant shows: Functional studies indicate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 applies to lack of segregation in multiple affected families. The evidence for this variant shows: No segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 applies to missense variants in a gene where only truncating variants cause disease. The evidence for this variant shows: It is a truncating variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 applies when variant is observed in trans with a pathogenic variant for a dominant gene. The evidence for this variant shows: No such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 applies to in‐frame indels in repetitive regions. The evidence for this variant shows: It is a frameshift duplication, not a repetitive-region indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 applies to benign computational evidence (REVEL<0.50 or SpliceAI≤0.20). The evidence for this variant shows: Although SpliceAI=0, the variant causes a frameshift leading to loss of function. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 applies when variant is found in a patient with an alternate molecular cause. The evidence for this variant shows: No alternate cause reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 applies to non‐publication of primary data by a reputable source. The evidence for this variant shows: No such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 applies to synonymous or intronic variants with SpliceAI≤0.20. The evidence for this variant shows: It is a frameshift variant. Therefore, this criterion is not applied.